This patent invention relates to vitamin D compounds, and more particularly to vitamin D derivatives substituted at the carbon 18 position.
Vitamin D is essential for life in higher animals. It is one of the important regulators of calcium and phosphorus and is required for proper development and maintenance of bone. However, during the past decade, the spectrum of activities promoted by 1,25-(OH)2D3 has been found to extend far beyond a role in calcium homeostasis. In addition to its action on the intestine, bone, kidney, and parathyroid glands to control serum calcium, this hormone has been shown to have important cell differentiating activity. Ostrem et al, Proc. Natl. Acad. Sci. USA, 84, 2610 (1987). Receptors for this hormone have been identified in several different target cells that respond to 1,25-(OH)2D3 with a diverse range of biological action. These newly discovered activities have suggested other therapeutic applications of 1,25-(OH)2D3 including hyperparathyroidism, psoriasis, cancer, and immune regulation.
Secondary hyperparathyroidism is a universal complication in patients with chronic renal failure. Because of its ability to suppress parathyroid hormone (PTH), 1,25-(OH)2D3 has been used with success in the treatment of secondary hyperparathyroidism, Slatopolsky, et al, xe2x80x9cMarked Suppression of Secondary Hyperparathroidism by Intravenous Administration of 1,25-dihydroxycholecalciferol in Uremic Patientsxe2x80x9d, J. Clin. Invest. 74:2136-2143, 1984. Its use is often precluded, however, by the development of hypercalcemia resulting from its potent action on intestinal absorption and bone mineral mobilization.
From the clinical point of view, one of the most difficult biochemical alterations to correct in hemodialysis patients is hyperphosphatemia. Patients on dialysis usually ingest approximately 1.0 to 1.4 grams of phosphorus per day. Since the maximum amount of phosphorus that is removed during each dialysis approximates 800 to 1,000 mg, Hou et al, xe2x80x9cCalcium and Phosphorus Fluxes During Hemodialysis with Low Calcium Dialysatexe2x80x9d, Am. J. Kidney Dis. 18:217-224, 1991, the remaining 2.5 to 3.5 grams of phosphorus ingested per week must be removed by other means. Thus, the use of phosphate binders such as calcium carbonate and calcium acetate are usually utilized to correct the hyperphosphatemia, Emmett et al, xe2x80x9cCalcium Acetate Control of Serum Phosphorus in Hemodialysis Patientsxe2x80x9d, Am. J. Kidney Dis. 24:544-550, 1991; Schaefer et al, xe2x80x9cThe Treatment of Uraemic Hyperphosphataemia with Calcium Acetate and Calcium Carbonate: A Comparative Studyxe2x80x9d, Nephrol Dial Transplant 6:170-175, 1991; Delmez et al, xe2x80x9cCalcium Acetate as a Phosphorus Binder in Hemodialysis Patientsxe2x80x9d, J. Am. Soc. Nephrol 3:96-102, 1992. Unfortunately, 1,25-(OH)2D3 not only increases the absorption of calcium but also of phosphorus, making hyperphosphatemia more difficult to be treated. Thus, the hyperphosphatemia induced in part by the action of 1,25-(OH)2D3 requires a further addition of calcium carbonate or calcium acetate, which can greatly increase the levels of serum ionized calcium. The high calcium-phosphate product that the patient may develop imposes a tremendous risk for the development of hypercalcemia and metastatic calcifications, Arora et al, xe2x80x9cCalcific Cardiomyopathy in Advanced Renal Failurexe2x80x9d, Arch. Inter. Med. 1335:603-605 1975; Rostand et al, xe2x80x9cMyocardial Calcification and Cardiac Dysfunction in Chronic Renal Failurexe2x80x9d, Am. J. Med. 85:651-657, 1988; Gipstein et al, xe2x80x9cCalcification and Cardiac Dysfunction in Chronic Renal Failurexe2x80x9d, Am. J. Med. 85:651-657, 1988: Gipstein et al, xe2x80x9cCalciphylaxis in Man A Syndrome of Tissue Necrosis and Vascular Calcifications in 11 Patients with Chronic Renal Failurexe2x80x9d, Arch. Intern. Med. 136:1273-1280, 176; Milliner et al, xe2x80x9cSoft Tissue Calcification in Pediatric Patients with End-stage Renal Diseasexe2x80x9d, Kidney Int. 38:931-936, 1990. Therefore, the treatment demands a decrease in the amount of 1,25-(OH)2D3 administered to the patient thus decreasing the effectiveness of 1,25-(OH)2D3 therapy for controlling PTH secretion. Thus, an analog of 1,25-(OH)2D3 that can suppress PTH with minor effects on calcium and phosphate metabolism would be an ideal tool for the control of secondary hyperparathyroidism, and the treatment of renal osteodystrophy.
Many structural analogs of 1,25-(OH)2D3 have been prepared and tested, including 1xcex1-hydroxyvitamin D3, 1xcex1-hydroxyvitamin D2, various side chain homologated D3 and D2 vitamins and fluorinated D3 and D2 analogs. Some of these compounds exhibit an interesting separation of activities in cell differentiation and calcium regulation. This difference in activity may be useful in the treatment of a variety of diseases as renal osteodystrophy, vitamin D-resistant rickets, osteoporosis, psoriasis, and certain malignancies.
Several analogs of 1,25-(OH)2D3 modified at the carbon 18 position are described in Nilsson et al, xe2x80x9cSynthesis and Biological Evaluation of 18-Substituted Analogs of 1xcex1,25-Dihydroxyvitamin D3xe2x80x9d, Bioorganic and Medicinal Chemistry Letters, Vol. 3, No. 9, pp. 1855-1858, 1993, and their in vitro biological behavior reported. 18-hydroxylated analogs are disclosed in Valles et al, xe2x80x9cFunctionalization of Vitamin D Metabolites at C-18 and Application to the Synthesis of 1xcex1,18,25-Trihydroxyvitamin D3 and 18,25-Dihydroxyvitamin D3xe2x80x9d, Tetrahedron Letters, Vol. 33, No. 11, pp. 1503-1506, 1992. 18-acetoxy analogs are described in Maynard et al, xe2x80x9c18-Substituted Derivatives of Vitamin D: 18-Acetoxy-1xcex1,25-Dihydroxyvitamin D3 and Related Analogues,xe2x80x9d J. Org. Chem., Vol. 57, No. 11, pp. 3214-3217, 1992, and are reported to be nearly devoid of in vivo biological activity.
Another class of vitamin D analogs, i.e. the so called 19-nor-vitamin D compounds, are characterized by the replacement of the A-ring exocyclic methylene group (carbon 19), typical of the vitamin D system, by two hydrogen atoms. Biological testing of such 19-nor-analogs (e.g., 1xcex1,25-dihydroxy-19-nor-vitamin D3) revealed a selective activity profile with high potency in inducing cellular differentiation, and very low intestinal calcemic transport activity as well as very low bone calcium mobilizing activity. Thus, these 19-nor compounds are potentially useful as therapeutic agents for the treatment of malignancies, (see U.S. Pat. No. 5,587,497) or the treatment of various skin disorders (see U.S. Pat. No. 5,578,587) as well as for the treatment of hyperphosphatemia (see U.S. Pat. No. 5,597,815), and hyperparathyroidism (see U.S. Pat. No. 5,246,925). Two different methods of synthesis of such 19-nor-vitamin D analogs have been described (Perlman et al., Tetrahedron Lett. 31, 1823 (1990); Perlman et al., Tetrahedron Lett. 32, 7663 (1991), and DeLuca et al., U.S. Pat. No. 5,086,191).
Recently, 2-substituted analogs of 1xcex1,25-dihydroxy-19-norvitamin D3 have also been synthesized, i.e. compounds substituted at 2-position with hydroxy or alkoxy groups (DeLuca et al, U.S. Pat. No. 5,536,713). These compounds exhibit interesting and selective activity profiles making them useful for the treatment of osteoporosis.
A series of 1xcex1-hydroxylated vitamin D compounds not known heretofore are the 19-nor-vitamin D analogs having a methyl or methylene group at the 18-position, i.e. 13-ethyl-18,19-dinor-vitamin D compounds and 13-vinyl-18,19-dinor-vitamin D compounds, particularly 13-ethyl-18,19-dinor-1xcex1,25-dihydroxyvitamin D3 and 13-vinyl-18,19-dinor-1xcex1,25-dihydroxyvitamin D3.
Structurally these novel analogs are characterized by the general formula I shown below: 
where Y1 and Y2, which may be the same or different, are each selected from the group consisting of hydrogen and a hydroxy-protecting group, R6 is selected from the group consisting of an ethyl or vinyl radical, and where the group R represents any of the typical side chains known for vitamin D type compounds.
The above novel compounds exhibit a desired, and highly advantageous, pattern of biological activity. These compounds are characterized by little, if any, intestinal calcium transport activity and little, if any, intestinal phosphorus absorption activity, as compared to that of 1xcex1,25-dihydroxyvitamin D3, as well as little, if any, bone calcium mobilizing activity, as compared to 1xcex1,25-dihydroxyvitamin D3. At the same time these compounds have the ability to suppress parathyroid hormone (PTH). Hence, these compounds are highly specific in their biological activity. Their preferential activity on supressing PTH and minimal intestinal calcium transport and bone calcium mobilization activities allows the in vivo administration of these compounds for the treatment of secondary hyperparathroidism and renal osteodystrophy. Because of their minimal intestinal phosphorus absorption activity, these compounds would be preferred therapeutic agents for the treatment of hyperphosphatemia in kidney disorder patients. The treatment may be transdermal, oral or parenteral. The compounds may be present in a composition in an amount from about 0.1 xcexc/gm to about 50 xcexcg/gm of the composition, and may be administered in dosages of from about 0.1 xcexcg/day to about 50 xcexcg/day.
The compounds of the invention are also especially suited for treatment and prophylaxis of human disorders which are characterized by an imbalance in the immune system, e.g. in autoimmune diseases, including multiple sclerosis, diabetes mellitus, host versus graft reaction, and rejection of transplants; and additionally for the treatment of inflammatory diseases, such as rheumatoid arthritis and asthma, as well as the improvement of bone fracture healing and improved bone grafts. Acne, alopecia, skin conditions such as dry skin (lack of dermal hydration), undue skin slackness (insufficient skin firmness), insufficient sebum secretion and wrinkles, and hypertension are other conditions which may be treated with the compounds of the invention.
The above compounds are also characterized by having high cell differentiation activity. Thus, these compounds also provide therapeutic agents for the treatment of psoriasis, or as an anti-cancer agent, especially against leukemia, colon cancer, breast cancer and prostate cancer. The compounds may be present in a composition to treat psoriasis in an amount from about 0.01 xcexcg/gm to about 100 xcexcg/gm of the composition, and may be administered topically, transdermally, orally or parenterally in dosages of from about 0.01 xcexcg/day to about 100 xcexcg/day.
This invention also provides novel intermediate compounds formed during the synthesis of the end products. Structurally, these novel intermediates have the general formula II shown below: 
where R represents any of the typical side chains known for vitamin D type compounds, and X is an acyl group, preferrably CH3COxe2x80x94.
This invention also provides a novel synthesis for the production of the end products of structure I.
This invention also provides a novel efficient synthesis for hydroxylated Windaus Grundmann ketone (8) through four steps from compound (1a) (see Scheme I). Hydroxylated Windaus Grundmann ketone (8) is an important fragment for the synthesis of 25-hydroxy vitamin D3.